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Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. link= Selleckchem Lenvatinib Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Selleckchem Lenvatinib Selleckchem Lenvatinib Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRβ sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.Large prehistoric rockslides tend to occur within spatio-temporal clusters suggesting a common trigger such as earthquake shaking or enhanced wet periods. Yet, trigger assessment remains equivocal due to the lack of conclusive observational evidence. Here, we use high-resolution lacustrine paleoseismology to evaluate the relation between past seismicity and a spatio-temporal cluster of large prehistoric rockslides in the Eastern Alps. Temporal and spatial coincidence of paleoseismic evidence with multiple rockslides at ~4.1 and ~3.0 ka BP reveals that severe earthquakes (local magnitude ML 5.5-6.5; epicentral intensity I0 VIII¼-X¾) have triggered these rockslides. A series of preceding severe earthquakes is likely to have progressively weakened these rock slopes towards critical state. These findings elucidate the role of seismicity in preparing and triggering large prehistoric rockslides in the European Alps, where rockslides and earthquakes typically occur in clusters. Such integration of multiple datasets in other formerly glaciated regions with low to moderate seismicity will improve our understanding of catastrophic rockslide drivers.During spaceflight, the central nervous system (CNS) is exposed to a complex array of environmental stressors. However, the effects of long-duration spaceflight on the CNS and the resulting impact to crew health and operational performance remain largely unknown. In this review, we summarize the current knowledge regarding spaceflight-associated changes to the brain as measured by magnetic resonance imaging, particularly as they relate to mission duration. Numerous studies have reported macrostructural changes to the brain after spaceflight, including alterations in brain position, tissue volumes and cerebrospinal fluid distribution and dynamics. link2 Changes in brain tissue microstructure and connectivity were also described, involving regions related to vestibular, cerebellar, visual, motor, somatosensory and cognitive function. Several alterations were also associated with exposure to analogs of spaceflight, providing evidence that brain changes likely result from cumulative exposure to multiple independent environmental stressors. Whereas several studies noted that changes to the brain become more pronounced with increasing mission duration, it remains unclear if these changes represent compensatory phenomena or maladaptive dysregulations. Future work is needed to understand how spaceflight-associated changes to the brain affect crew health and performance, with the goal of developing comprehensive monitoring and countermeasure strategies for future long-duration space exploration.Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-'reading' bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.Pelvic radiograph (PXR) is essential for detecting proximal femur and pelvis injuries in trauma patients, which is also the key component for trauma survey. None of the currently available algorithms can accurately detect all kinds of trauma-related radiographic findings on PXRs. Here, we show a universal algorithm can detect most types of trauma-related radiographic findings on PXRs. We develop a multiscale deep learning algorithm called PelviXNet trained with 5204 PXRs with weakly supervised point annotation. PelviXNet yields an area under the receiver operating characteristic curve (AUROC) of 0.973 (95% CI, 0.960-0.983) and an area under the precision-recall curve (AUPRC) of 0.963 (95% CI, 0.948-0.974) in the clinical population test set of 1888 PXRs. The accuracy, sensitivity, and specificity at the cutoff value are 0.924 (95% CI, 0.912-0.936), 0.908 (95% CI, 0.885-0.908), and 0.932 (95% CI, 0.919-0.946), respectively. PelviXNet demonstrates comparable performance with radiologists and orthopedics in detecting pelvic and hip fractures.The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.Stochastic processes govern the time evolution of a huge variety of realistic systems throughout the sciences. A minimal description of noisy many-particle systems within a Markovian picture and with a notion of spatial dimension is given by probabilistic cellular automata, which typically feature time-independent and short-ranged update rules. Here, we propose a simple cellular automaton with power-law interactions that gives rise to a bistable phase of long-ranged directed percolation whose long-time behaviour is not only dictated by the system dynamics, but also by the initial conditions. In the presence of a periodic modulation of the update rules, we find that the system responds with a period larger than that of the modulation for an exponentially (in system size) long time. This breaking of discrete time translation symmetry of the underlying dynamics is enabled by a self-correcting mechanism of the long-ranged interactions which compensates noise-induced imperfections. Our work thus provides a firm example of a classical discrete time crystal phase of matter and paves the way for the study of novel non-equilibrium phases in the unexplored field of driven probabilistic cellular automata.In metabolic engineering, loss-of-function experiments are used to understand and optimise metabolism. A conditional gene inactivation tool is required when gene deletion is lethal or detrimental to growth. link3 Here, we exploit auxin-inducible protein degradation as a metabolic engineering approach in yeast. We demonstrate its effectiveness using terpenoid production. First, we target an essential prenyl-pyrophosphate metabolism protein, farnesyl pyrophosphate synthase (Erg20p). Degradation successfully redirects metabolic flux toward monoterpene (C10) production. Second, depleting hexokinase-2, a key protein in glucose signalling transduction, lifts glucose repression and boosts production of sesquiterpene (C15) nerolidol to 3.5 g L-1 in flask cultivation. Third, depleting acetyl-CoA carboxylase (Acc1p), another essential protein, delivers growth arrest without diminishing production capacity in nerolidol-producing yeast, providing a strategy to decouple growth and production. These studies demonstrate auxin-mediated protein degradation as an advanced tool for metabolic engineering. It also has potential for broader metabolic perturbation studies to better understand metabolism.The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. link2 Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-β receptor (LTβR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTβR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTβR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTβR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTβR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.A graphdiyne-based artificial synapse (GAS), exhibiting intrinsic short-term plasticity, has been proposed to mimic biological signal transmission behavior. The impulse response of the GAS has been reduced to several millivolts with competitive femtowatt-level consumption, exceeding the biological level by orders of magnitude. Most importantly, the GAS is capable of parallelly processing signals transmitted from multiple pre-neurons and therefore realizing dynamic logic and spatiotemporal rules. It is also found that the GAS is thermally stable (at 353 K) and environmentally stable (in a relative humidity up to 35%). link3 Our artificial efferent nerve, connecting the GAS with artificial muscles, has been demonstrated to complete the information integration of pre-neurons and the information output of motor neurons, which is advantageous for coalescing multiple sensory feedbacks and reacting to events. Our synaptic element has potential applications in bioinspired peripheral nervous systems of soft electronics, neurorobotics, and biohybrid systems of brain-computer interfaces.
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